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Gastrointestinal Hormones & Neurotransmitters Bayliss and Starling discovered secretin in 1902 GI Function: absorptive, secretory, digestive, motor and trophic actions on GI tract & other organs, immunological. GI tract specialized cells Specialized chromaffin (enterochromaffin (EC) cells were described by histologists in >1870. Other cells are termed enterochromaffin-like (ECL) cells ECL ? cells that stain with silver (Argyrophilic), Grimelius, Bodian & Seivier-Munger Methods. (Histamine is an ECL cell GI hormone) EC cells are scattered in the epithelium lining the gastric glands, intestinal crypts and villi. Generally, secretory granules are a storage source for apocrine release. Secretory granules are released in one of 4 modes (paracrine, Neurocrine [neurotransmitters], Open or Closed Endocrine) Pearse?s Concept (Nature 1976; 262:92-92) nerves and EC cells regarded as two intergraded systems Gastrointestinal Peptides The cells of the GI tract secrete many peptides. The GI hormones are polypeptides that are secreted by endocrine cells located in the mucosa of GI organs. These cells are dispersed throughout the mucosal layer. Some of these polypeptides clearly function as hormones, because they are secreted into the circulation and transported to their target tissue. Other polypeptides act as paracrines, being secreted into the interstitial space and diffusing to nearby cells, where they have their action. Some GI polypeptides are neurocrines. These are secreted by cells of the enteric nervous system and act as neurotransmitters. Some of the GI polypeptides are found in both endocrine and nerve cells and thus are difficult to classify. In the following section, the peptides will be discussed in the class where they seem most likely to have their major physiologic role. Many of the peptides found in the GI system are also found in the brain, where they may act as neurotransmitters. Four of the many peptides secreted by the GI endocrine cells meet the physiologic requirements for hormonal status. The established hormones satisfy the following criteria. A physiologic stimulus associated with the ingestion and processing of food causes the release of the peptide from GI endocrine cells. The peptide enters the circulation and causes one or more actions at target tissues in the GI tract. The action persists despite denervation of the affected GI structure. The substance has been isolated from the site of stimulus application and its chemical structure has been identified. It produces the physiologic response when injected into the circulation at physiologic levels. A physiologic response is defined as one that occurs at a serum concentration within the range normally reached following ingestion of a meal. The established hormones are gastrin, CCK, secretin, and GIP. Established GI Hormones GIP=Incretin ID and Classification of Cell Types One Hormone, one cell ? is still a working basis for cell classification, but it is not without exceptions (POMC; Glucagon; etc) Increasing evidence that multiple hormones may be produced and secreted (POMC; Glucagon; etc) Clear evidence of neuroendocrine production of more than one factor per neuron. Localization of Gut Hormones Gastrointestinal hormones are peptides are found in endocrine cells and nerves. All are composed of a single peptide chain with the exception of insulin. Main GI stimulation of GI Hormones Web Data base for G-protein hormone receptors : www.qpcr.org/7tm Neuropeptides of the GI Tract As many as six peptides can be found in a single neuron Illustration of the major elements in chemical synaptic transmission. An electrochemical wave called an action potential travels along the axon of a neuron. When the wave reaches a synapse, it provokes release of a puff of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of another neuron, on the opposite side of the synapse. Incretins (GIP & GLP-1 &-2) Factor produced by the intestinal mucosa in response to nutrient ingestion that is capable of stimulating the release of substances from the endocrine pancreas and thereby reducing blood glucose levels. Incretins and incretin mimetics are being utilized in Type 2 diabetes. Gastrointestinal tract Total Length ~ 4.5 m Esophagous 25 cm Stomach 23 cm Small Intestine 2.77 m Duodenum 22 cm Jejuno=ileum 2.55 m Large Intestine 1.1 m Tissue layers of the GI tract Role of the Central Nervous System Although the enteric nervous system is capable of sustaining GI function independently of extrinsic nervous control, the CNS has a strong influence on GI secretory and muscle functions. The autonomic nerves carry both afferent and efferent fibers. Reflex activity controlling GI functions can thus be integrated both at the level of the enteric nervous system plexuses and in the autonomic ganglia, at the level of the spinal cord and at higher centers. Parasympathetic stimulation is, as a general rule, excitatory to both secretory and motor functions. However, some vagal fibers to the upper GI tract synapse on inhibitory neurons of the enteric plexuses and account for vagal inhibition of the lower esophageal sphincter and the cardia of the stomach. Sympathetic stimulation is generally inhibitory to the GI smooth muscle, with the exception of its actions at sphincters. In the vascular beds of the GI tract, as elsewhere, sympathetic stimulation causes vasoconstriction CNS centers have been identified that play major roles in initiating and integrating several GI functions. Integrative functions of the CNS are required for swallowing, vomiting, and defecation, all of which involve the coordinated activity of skeletal muscle and GI smooth muscle and all of which are impaired following vagotomy. Emotional responses like anxiety, anger, and fear all have effects on the GI system that are mediated through the CNS, as are the integration of hunger, food intake, and satiety. Enteric nervous system (solely within GI tissue) are clustered one of two plexus Only in Sm & Lg Intestine Enteric (Intrinsic) Nervous System Auerbach?s Meissner?s Extrinsic (Autonomic) Nervous System Enteric nervous system and sympathetic and parasympathetic neurons innervating the gastric mucosa Parasympathetic Innervation of the GI Tract Sympathetic Innervation of the GI Tract Neurocrines; Neurotransmitters A number of substances have been identified, by their presence in neurons of the enteric nervous system, as possible neurotransmitters. Many of these substances are found in the brain, where they are also believed to act as neurotransmitters. Acetylcholine is a major neurotransmitter released from motor neurons of the enteric nervous system. It excites smooth muscle and secretory cells. Norepinephrine generally acts to inhibit GI activity, and its actions are mediated by its effects on ganglion cells of the enteric nervous system plexuses. It may act by inhibiting release of acetylcholine or by causing release of an inhibitory transmitter from interneurons in the plexuses or from the enteric motor neurons. The list of putative transmitters is long and includes peptides such as vasoactive intestinal peptide (VIP), substance P, gastrin-releasing peptide (GRP), enkephalin, CCK-8, neurotensin, somatostatin, and neuropeptide Y. Nonpeptidergic substances such as ATP, adenosine, and serotonin also have been reported to be released from enteric nerves. The physiologic significance of most of these putative transmitters is uncertain at present. Anatomy and histology of the duodenum A large # of trophic factors are produced locally and released in a paracrine manner; cells such as fibroblasts, endothelial cells, epithelial cells, leucocytes, etc. EC Cells . Villi LYMPHATIC AND BLOOD VENOUS DRAINAGE OF THE ALIMENTARY TRACT Oxyntic pit Antral pit GASTROINTESTINAL HORMONES (GUT HORMONES) SECRETIN CHOLECYSTOKININ (CCK) GASTRIN GIP Amino acid sequences of CCK and Gastrin CCK full bio-activity = 8 AA, but 33, 38 and 59 AA CCKs are present Gastrin has 3 forms, G34 (Circulation), G17 (gastric) and G14 ? the latter has full bio-activity # sulfation of the Tyr is mandatory for bio-activity as well as protecting the peptide from proteolytic digest and liver passage *sulfation at Tyr is not mandatory for full bio-activity Gastrin/CCK Family Gastrin is secreted by the G cells, which are present in the antrum of the stomach and in the duodenum. About 90% of GI gastrin is in the antral tissue and 10 % is in the duodenum. Gastrin exists in three biologically active forms: G-14, a 14-amino acid peptide known as mini gastrin; G-17, a 17-amino acid peptide also known as little gastrin; and G-34, a 34-amino acid peptide known as big gastrin. In humran, the G17 & G37 are the main circulating forms. Their plasma concentration rises during the digestive phase, and it is believed to be the main physiologic form of the hormone that is released in response to a meal. Gastrin/CCK Family CCK was first isolated as CCK33, but CCK58 is best characterized. Many other forms are known that are proteolytic fragments of CCK58 (4, 8, 22, 33). In humans, CCK58, CCK33 and CCK8 are predominant. CCK/Gastrin Receptors (G-proteins) CCK-A (CCK-1) ? 49.6 kDa, highly glycosylated; Pancreas & Gallbladder location- high affinity CCK over gastrin Gallbladder contraction & pancreatic secretion CCK-B/Gastrin (CCK-2) ? 48.9 kDa, highly glycosylated; Brain/neuronal tissues; neuroleptic (antipsychotic) activity; satiety signal, equal CCK & gastrin affinity Two different CCK Receptors Main Gastrin Action Direct and indirect actions of secretagoguses on parietal cells Main Gastrin Release Regulation of gastric-acid secretion in the stomach Main CCK Action Main CCK Release Factors Stimulation of protein secretion from pancreatic acinar cell Gastrin-Cholecystokinin Family of GI Peptides Phases of pancreatic secretion: Cephalic-gastric phases Pancreatic secretion: Intestinal phase Secretin Family Secretin has only one form (27AA) Stimulated by acid (low pH) in the duodenum/jejunum Biological Action ? stimulate secretion of water/bicarb from pancreas (via the Secretin receptor (G-protein); stimulate pepsinogen release from the peptic chief cells GIP ? gastrin inhibiting peptide; Glucose-dependent Insulinotropic Polypeptide (inhibits gastric acid and pancreatic secretion- stim insulin release) VIP ? relax lower sphincter, inhibit gastic acid secretion, increase gut motility, increase blood flow Secretin Family of GI Peptides Main action of Secretin Actions of GIP GIP was first studied as an enterogastrone. An enterogastrone is a substance released from the intestinal mucosa by acid, fat, or hyperosmolarity and carried to the stomach, where it acts to inhibit gastric acid secretion or gastric motility. Although original observations suggested this function for GIP and gave it its name, gastric inhibiting protein, its inhibiting action is now controversial. GIP has been shown to inhibit gastrin release and acid secretion; however, physiologic levels of GIP are not sufficient to account completely for the fat-induced inhibition of acid secretion. The major physiologic action of GIP is to cause insulin release. This action occurs only if the GIP release is accompanied by glucose absorption and increased serum glucose concentration. The threshold for the insulin response is an increase of about 20 mg/dL in serum glucose. This has resulted in a second name for GIP, Glucose-dependent Insulinotropic Peptide. Release of GIP Glucose in the upper small intestine causes GIP release. GIP also is released by long-chain fatty acids and their monoglycerides. Certain amino acids (arginine, histidine, isoleucine, leucine, lysine and threonine) are effective in releasing GIP. This is a different group of amino acids than those causing release of gastrin and CCK. Neither acidification of the upper small intestine nor a neural component are involved in GIP release. Its release may be inhibited by high levels of insulin or glucagon, but the physiologic significance of this is not clear GIP biological action GLP-1 biological actions; RLP-1R except liver, fat, and muscle Somatostatin blood hormone, paracrine, and neuropeptide Two forms, SS-28; SS-14 (hypothalamus & pancreatic D cells; stomach, duodenum, colon) Both forms biologically active Simulated release ? pancreas=glucose, arginine GI tract = meal, fat, acid Hormones secreted during interdigestive periods: Motilin/Ghrelin Ghrelin is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiety before it would normally occur. Motilin main function is to increase the migrating myoelectric complex component of gastrointestinal motility and stimulate the production of pepsin. Motilin is also called "Housekeeper of the gut" because it improves peristalsis in the small intestine and clears out the gut to prepare for the next meal. A high level of motilin secreted between meals into the blood stimulates the contraction of the fundus and antrum and accelerates gastric emptying. It then contracts the gallbladder and increases the squeeze pressure of the lower esophageal sphincter. Other functions of motilin include increasing the release of pancreatic polypeptide and somatostatin Pancreatic Polypeptide (PPP) is a linear peptide with 36 amino acids. It is produced by both pancreatic islet cells and endocrine cells scattered throughout the exocrine pancreas.Protein digestion products, particularly phenylalanine and tryptophan, in the lumen of the gut are the most potent releasers; fat and carbohydrate are less effective. PPP also is released by vagal stimulation, acetylcholine and stomach distension. Pancreatic Polypeptide PPP PPP Zollinger-Ellison Syndrome Gastrinomas; A gastrinoma is a tumor that secretes gastrin. Zollinger & Ellison 1955. Ann. Surg 142:709 Severe ulcer disease, gastric acid hypersecretion and non-beta islet cell tumors of the pancreas Both sulfated and non-sulfated forms present Gastric-parietal cell mass is expanded 3-6X Gastrinoma Carcinoid Syndrome Intestinal tumors that are derived from enterochromaffin cells Gut endocrine tumors are uncommon (1/200,000) Carcinoid tumors are discrete, yellow, well-circumscribed tumors that can occur anywhere along the gastrointestinal tract and in the lung. They most commonly affect the appendix, ileum, and rectum. Carcinoids are tumors of neuroendocrine nature, that originate in the cells of the neuroendocrine system and are characterized by production of serotonin (5-hydroxytryptamine; 5-HT).

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